biostudies-literatureIssigonis MWelch Foundation (The Welch Foundation)NICHD NIH HHSHoward Hughes Medical InstituteNIAID NIH HHSHHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentHHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)HHS | NIH | National Institute of Allergy and Infectious DiseasesWelch FoundationHoward Hughes Medical Institute (HHMI)e2321349121https://www.ebi.ac.uk/biostudies/studies/S-EPMC11214079biostudies-literatureUnknown121(26)Germ cells are regulated by local microenvironments (niches), which secrete instructive cues. Conserved developmental signaling molecules act as niche-derived regulatory factors, yet other types of niche signals remain to be identified. Single-cell RNA-sequencing of sexual planarians revealed niche cells expressing a nonribosomal peptide synthetase (<i>nrps</i>). Inhibiting <i>nrps</i> led to loss of female reproductive organs and testis hyperplasia. Mass spectrometry detected the dipeptide β-alanyl-tryptamine (BATT), which is associated with reproductive system development and requires <i>nrps</i> and a monoamine-transmitter-synthetic enzyme Aromatic L-amino acid decarboxylase (AADC) for its production. Exogenous BATT rescued the reproductive defects after <i>nrps</i> or <i>aadc</i> inhibition, restoring fertility. Thus, a nonribosomal, monoamine-derived peptide provided by niche cells acts as a critical signal to trigger planarian reproductive development. These findings reveal an unexpected function for monoamines in niche-germ cell signaling. Furthermore, given the recently reported role for BATT as a male-derived factor required for reproductive maturation of female schistosomes, these results have important implications for the evolution of parasitic flatworms and suggest a potential role for nonribosomal peptides as signaling molecules in other organisms.Proceedings of the National Academy of Sciences of the United States of AmericaA niche-derived nonribosomal peptide triggers planarian sexual development.PMC11214079I-1948-20240404R01 AI150776Investigator AwardR01 043403R01 HD043403Browder KLIssigonis MNewmark PACollins JJChen RfalseA niche-derived nonribosomal peptide triggers planarian sexual development.Germ cells are regulated by local microenvironments (niches), which secrete instructive cues. Conserved developmental signaling molecules act as niche-derived regulatory factors, yet other types of niche signals remain to be identified. Single-cell RNA-sequencing of sexual planarians revealed niche cells expressing a nonribosomal peptide synthetase (<i>nrps</i>). Inhibiting <i>nrps</i> led to loss of female reproductive organs and testis hyperplasia. Mass spectrometry detected the dipeptide β-alanyl-tryptamine (BATT), which is associated with reproductive system development and requires <i>nrps</i> and a monoamine-transmitter-synthetic enzyme Aromatic L-amino acid decarboxylase (AADC) for its production. Exogenous BATT rescued the reproductive defects after <i>nrps</i> or <i>aadc</i> inhibition, restoring fertility. Thus, a nonribosomal, monoamine-derived peptide provided by niche cells acts as a critical signal to trigger planarian reproductive development. These findings reveal an unexpected function for monoamines in niche-germ cell signaling. Furthermore, given the recently reported role for BATT as a male-derived factor required for reproductive maturation of female schistosomes, these results have important implications for the evolution of parasitic flatworms and suggest a potential role for nonribosomal peptides as signaling molecules in other organisms.2024-01-01T00:00:00Z2024 Jun2026-03-27T16:09:03.49Z2025-08-30T03:05:37.393ZS-EPMC112140793888915210.1073/pnas.2321349121